RESUMO
Sustained signal activation by hydroxyl radicals (â OH) has great significance, especially for tumor treatment, but remains challenging. Here, a built-in electric field (BIEF)-driven strategy was proposed for sustainable generation of â OH, thereby achieving long-lasting chemodynamic therapy (LCDT). As a proof of concept, a novel Janus-like Fe@Fe3 O4 -Cu2 O heterogeneous catalyst was designed and synthesized, in which the BIEF induced the transfer of electrons in the Fe core to the surface, reducing ≡Cu2+ to ≡Cu+ , thus achieving continuous Fenton-like reactions and â OH release for over 18â h, which is approximately 12 times longer than that of Fe3 O4 -Cu2 O and 72 times longer than that of Cu2 O nanoparticles. In vitro and in vivo antitumor results indicated that sustained â OH levels led to persistent extracellular regulated protein kinases (ERK) signal activation and irreparable oxidative damage to tumor cells, which promoted irreversible tumor apoptosis. Importantly, this strategy provides ideas for developing long-acting nanoplatforms for various applications.
Assuntos
Nanopartículas , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Nanopartículas/química , Radical Hidroxila/metabolismo , Estresse Oxidativo , Peróxido de Hidrogênio/metabolismo , Linhagem Celular TumoralRESUMO
Designing luminescence lifetime sensors in the second near-infrared (NIR-II) window is a great challenge due to the difficult structural construction. Here, we report a tumor redox responsive and easily synthesized material, amorphous manganese oxide (MnOx ) with indirect band gap of 1.02â eV, as an energy acceptor to build a luminescence resonance energy transfer (LRET) toolbox for universally regulating NIR-I to NIR-II luminescence lifetimes of lanthanide nanoparticles, in which energy transfer is based on matched energy gap instead of conventional overlapped spectra. We further utilize ytterbium (Yb3+ )-doped YbNP@MnOx as an NIR-II luminescence lifetime sensor to realize in vitro quantitative redox visualization with relative errors under 5 % in samples covered with mouse skin. Furthermore, HepG2 cells and tumors with high redox state have been accurately distinguished by NIR-II luminescence lifetime imaging. The quantified intracellular and intratumor glutathione (GSH) levels are highly consistent with the commercial kit results, illustrating the reliable redox visualization ability in biological tissue.
Assuntos
Elementos da Série dos Lantanídeos , Nanopartículas Metálicas , Nanopartículas , Neoplasias , Camundongos , Animais , Elementos da Série dos Lantanídeos/química , Luminescência , Nanopartículas/química , Glutationa , Espectroscopia de Luz Próxima ao Infravermelho , OxirreduçãoRESUMO
Frequency shift surface-enhanced Raman scattering (SERS) achieves multiplex microRNA sensing for early serological diagnosis of, and discrimination between, primary liver cancers in a patient cohort for whom only biopsy is effective clinically. Raman reporters microprinted on plasmonic substrates shift their vibrational frequencies upon biomarker binding with a dynamic range allowing direct, multiplex assay of serum microRNAs and the current best protein biomarker, α-fetoprotein. Benchmarking against current gold-standard polymerase chain reaction and chemiluminescence methods validates the assay. The work further establishes the frequency shift approach, sensing shifts in an intense SERS band, as a viable alternative to conventional SERS sensing which involves the more difficult task of resolving a peak above noise at ultralow analyte concentrations.
Assuntos
Detecção Precoce de Câncer , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , MicroRNAs/sangue , Análise Espectral Raman/métodos , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Estudos de Coortes , Técnicas Eletroquímicas/métodos , Humanos , Luminescência , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , alfa-Fetoproteínas/metabolismoRESUMO
The clearance of senescent cells may be detrimental to low cell density diseases, such as intervertebral disc degeneration (IVDD), and rejuvenating these cells presents a formidable obstacle. In this study, we investigate a mild-alkalization strategy employing magnesium boride-alginate (MB-ALG) hydrogels to rejuvenate senescent cells associated with age-related diseases. MB-ALG hydrogels proficiently ensnare senescent cells owing to their surface roughness. The hydrolysis of MB-ALG hydrogels liberates hydroxide ions (OH-), effecting a transition from an acidic microenvironment (pH â¼ 6.2) to a mildly alkaline state (pH â¼ 8.0), thereby fostering senescent cell proliferation via activation of the PI3K/Akt/mTOR pathway. Additionally, H2 aids in ROS clearance, which reduces cellular oxidative stress. And, Mg2+ rejuvenates senescent cells by inhibiting Ca2+ influx and fine-tuning the sirt1-p53 signaling pathways. Both in vitro and in vivo experiments conducted on rat intervertebral discs corroborate the sustained antisenescence and rejuvenation properties of MB-ALG hydrogels, with effects persisting for up to 12 weeks postoperation. These discoveries elucidate the role of mild-alkalization in dictating cellular destiny and provide key insights for addressing age-related diseases.
RESUMO
In vivo cross-linking of nanoparticles is widely used to increase accumulation of therapeutic agents at tumor site for enhanced therapy. However, the components in nanoplatforms usually only play for one role and are independent of each other, unable to amplify their biofunctions. Herein, a complementary functioning tumor microenvironment triggered, supramolecular coordination-induced nanoparticle cross-linking strategy is constructed for enhanced photodynamic therapy. Manganese oxide (MnOx ) and polyhydroxy photosensitizer hypericin (Hyp) are coated and loaded onto lanthanide-doped upconversion nanoparticles (UCNPs) to form transformable UCNP@MnOx -Hyp. In CT26 mouse colon cancer cells and xenograft tumors, UCNP@MnOx -Hyp is reduced by glutathione and H2 O2 , releasing Mn2+ and Hyp for in situ cross-linking to transform to UCNP@Mn2+ -Hyp. Compared to the simple photosensitizer-loaded UCNP@PEI-Hyp, the Mn2+ -Hyp coordination redshifts absorbance of Hyp and improves the energy transfer efficiency from UCNPs to Hyp (5.6-fold). In turn, the supramolecular coordination-induced UCNPs cross-linking exhibits enhanced luminescence recovery and increased intracellular accumulation of both UCNPs and Hyp, thus enhancing the photodynamic therapy efficacy both at cellular level (2.1-fold) and in vivo, realizing the function amplification of each component after responsive transformation and offering a new avenue for enhanced cancer therapy.
Assuntos
Nanopartículas , Neoplasias , Fotoquimioterapia , Camundongos , Animais , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Linhagem Celular Tumoral , Células HeLa , Neoplasias/tratamento farmacológicoRESUMO
Circadian rhythm (CR) disruption contributes to tumor initiation and progression, however the pharmacological targeting of circadian regulators reversely inhibits tumor growth. Precisely controlling CR in tumor cells is urgently required to investigate the exact role of CR interruption in tumor therapy. Herein, based on KL001, a small molecule that specifically interacts with the clock gene cryptochrome (CRY) functioning at disruption of CR, we fabricated a hollow MnO2 nanocapsule carrying KL001 and photosensitizer BODIPY with the modification of alendronate (ALD) on the surface (H-MnSiO/K&B-ALD) for osteosarcoma (OS) targeting. The H-MnSiO/K&B-ALD nanoparticles reduced the CR amplitude in OS cells without affecting cell proliferation. Furthermore, nanoparticles-controlled oxygen consumption by inhibiting mitochondrial respiration via CR disruption, thus partially overcoming the hypoxia limitation for photodynamic therapy (PDT) and significantly promoting PDT efficacy. An orthotopic OS model demonstrated that KL001 significantly enhanced the inhibitory effect of H-MnSiO/K&B-ALD nanoparticles on tumor growth after laser irradiation. CR disruption and oxygen level enhancement induced by H-MnSiO/K&B-ALD nanoparticles under laser irradiation were also confirmed in vivo. This discovery first demonstrated the potential of CR controlling for tumor PDT ablation and provided a promising strategy for overcoming tumor hypoxia.
RESUMO
"Structure subserves function" is one fundamental biological maxim, and so the biological membrane that delimits the regions primarily serves as the margin between life and death for individual cells. Here, an Oswald ripening mechanism-guided solvothermal method was proposed for the synthesis of uniform MnS nanocapsules assembled with metastable γ-MnS nanocrystals. Through designing the physicochemical properties, MnS nanocapsules would disaggregate into small γ-MnS nanocrystals in a tumor acidic environment, with the surface potential switched from negative to positive, thus showing conspicuous delivery performance. More significantly, the specific accumulation of Mn2+ in mitochondria was promoted due to the downregulation of mitochondrial calcium uptake 1 (MICU1) by the formed H2S, thus leading to serious mitochondrial Mn-poisoning for membrane permeability increase and then tumor apoptosis. This study provides a synthesis strategy of metal sulfide nanocapsules and encourages multidisciplinary researchers to focus on ion-cancer crosstalk for the development of an antitumor strategy.
Assuntos
Membranas Mitocondriais , Nanocápsulas , Membranas Mitocondriais/metabolismo , Mitocôndrias , Apoptose , PermeabilidadeRESUMO
Upconversion nanoparticles (UCNPs) and MnO2 composite materials have broad prospects in biological applications due to their near-infrared (NIR) imaging capability and tumor microenvironment-responsive features. Nevertheless, the synthesis of such composite nanoplatforms still faces many hurdles such as redundant processing and uneven coatings. Here, we explored a simple, rapid, and universal method for precisely controlled coating of mesoporous MnO2 (mMnO2) using poly(ethylene imine) as a reducing agent and potassium permanganate as a manganese source. Using this strategy, a mMnO2 shell was successfully coated on UCNPs. We further modified the mMnO2-coated UCNPs (UCNP@mMnO2) with a photosensitizer (Ce6), cisplatin drug (DSP), and tumor targeting pentapeptide (TFA) to obtain a nanoplatform UCNP/Ce6@mMnO2/DSP-TFA for treating spinal metastasis of nonsmall cell lung cancer (NSCLC-SM). The utilization of both upconversion and downconversion luminescence of UCNPs with different NIR wavelengths can avoid the simultaneous initiation of NIR-II in vivo imaging and tumor photodynamic therapy, thus reducing damage to normal tissues. This platform achieved a high synergistic effect of photodynamic therapy and chemotherapy. This leads to beneficial antitumor effects on the therapy of NSCLC-SM.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Fotoquimioterapia , Neoplasias da Coluna Vertebral , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Raios Infravermelhos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Manganês/farmacologia , Óxidos/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias da Coluna Vertebral/tratamento farmacológico , Microambiente TumoralRESUMO
The tumor microenvironment is a complex milieu where neurons constitute an important non-neoplastic cell type. From "cancer neuroscience," the crosstalk between tumors and neurons favors the rapid growth of both, making the cancer-nerve interaction a reciprocally beneficial process. Thus, cancer-nerve crosstalk may provide new targets for therapeutic intervention against cancer and cancer-related symptoms. We proposed a nerve-cancer crosstalk blocking strategy for metastatic bone cancer pain treatment, achieved by Mg/Al layered-double-hydroxide nanoshells (Mg/Al-LDH) with AZ-23 loaded inside and alendronate decorated outside. The pain-causing H+ is rapidly eliminated by the LDH, with neurogenesis inhibited by the antagonist AZ-23. As positive feedback, the decreased pain reverses the nerve-to-cancer Ca2+ crosstalk-related cell cycle, dramatically inhibiting tumor growth. All experiments confirm the improved pain threshold and enhanced tumor inhibition. The study may inspire multidisciplinary researchers to focus on cancer-nerve crosstalk for treating cancer and accompanied neuropathic diseases.
Assuntos
Neoplasias Ósseas , Dor do Câncer , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Dor do Câncer/tratamento farmacológico , Dor do Câncer/metabolismo , Humanos , Neurônios/metabolismo , Dor/metabolismo , Microambiente TumoralRESUMO
Because of the low tissue penetration depth and poor photostability of organic cyanine dye, in addition to environmental interference, it is a great challenge to monitor the degree of drug-induced hepatotoxicity by the in vivo detection of peroxynitrite (ONOO-). Herein, we fabricated heptamethine cyanine dye (P-cy7)-coordinated upconversion nanoparticles (UCNPs), namely UCY7, as a fluorescent nanoprobe for evaluating drug-induced hepatotoxicity. Due to the luminescence resonance energy transfer (LRET) between UCNPs and the cyanine dye (P-cy7), the irradiation changed from visible light at 660 nm to near infrared (NIR) light at 980 nm; therefore, the issues of poor photostability and severe photobleaching of cyanine dye can be effectively solved. After injecting via the tail vein, the nanoprobes are rapidly concentrated in the liver. Since the level of ONOO- is up-regulated during the drug-induced liver injury, the LRET between UCNPs and P-cy7 is disrupted to release the upconversion luminescence at 656 nm, while the upconversion luminescence at 800 nm remains constant, thus achieving the ratio-fluorescent imaging (RFLI) of ONOO- in the liver to calibrate the influence of the environment. In addition, the reduction in the absorption of nanoprobes in the presence of ONOO- allows for sensitive photoacoustic imaging (PAI). Based on the RFLI and PAI of the liver, the real-time monitoring and accurate diagnosis of different degrees of hepatotoxicity using the model of Acetaminophen (APAP) induction was achieved successfully, providing a new approach for the clinical evaluation of drug-induced hepatotoxicity.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Corantes Fluorescentes/química , Ácido Peroxinitroso/metabolismo , Técnicas Fotoacústicas/métodos , Acetaminofen/toxicidade , Animais , Carbocianinas/química , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Feminino , Transferência Ressonante de Energia de Fluorescência , Raios Infravermelhos , Fígado/química , Fígado/metabolismo , Fígado/patologia , Nanopartículas Metálicas/química , Camundongos , Camundongos Endogâmicos BALB C , Ácido Peroxinitroso/química , Regulação para CimaRESUMO
Manganese dioxide (MnO2) nanostructures have aroused great interest among analytical and biological medicine researchers as a unique type of tumor microenvironment (TME)-responsive nanomaterial. However, reliable approaches for synthesizing yolk-shell nanostructures (YSNs) with mesoporous MnO2 shell still remain exciting challenges. Herein, a YSN (size, â¼75 nm) containing a mesoporous MnO2 shell and Er3+-doped upconversion/downconversion nanoparticle (UCNP) core with a large cavity is demonstrated for the first time. This nanostructure not only integrates diverse functional components including MnO2, UCNPs, and YSNs into one system but also endows a size-controllable hollow cavity and thickness-tunable MnO2 layers, which can load various guest molecules like photosensitizers, methylene blue (MB), and the anticancer drugs doxorubicin (DOX). NIR-II fluorescence and photoacoustic (PA) imaging from UCNP and MB, respectively, can monitor the enrichment of the nanomaterials in the tumors for guiding chemo-photodynamic therapy (PDT) in vivo. In the TME, degradation of the mMnO2 shell by H2O2 and GSH not only generates Mn2+ for tumor-specific T1-MR imaging but also releases O2 and drugs for tumor-specific treatment. The result confirmed that imaging-guided enhanced chemo-PDT combination therapy that benefited from the unique structural features of YSNs could substantially improve the therapeutic effectiveness toward malignant tumors compared to monotherapy.
Assuntos
Portadores de Fármacos/química , Compostos de Manganês/química , Nanoestruturas/química , Óxidos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Células HeLa , Humanos , Raios Infravermelhos , Azul de Metileno/química , Azul de Metileno/farmacologia , Azul de Metileno/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Porosidade , Espécies Reativas de Oxigênio/metabolismo , Transplante HeterólogoRESUMO
We report a highly sensitive and selective surface-enhanced Raman scattering (SERS)-based detection of aqueous Zn(ii) ions (limit of detection 10-14 M). Spectral changes for a silver nanoparticle-bound Raman reporter upon Zn(ii) chelation constitutes the assay, which is applied to drinking water and to measurements of cellular uptake of Zn(ii).
Assuntos
Meios de Cultura/química , Água Potável/química , Zinco/análise , Meios de Cultura/metabolismo , Células HeLa , Humanos , Nanopartículas Metálicas/química , Prata/química , Análise Espectral Raman , Propriedades de Superfície , Zinco/metabolismoRESUMO
We present a SERS-based method for the detection of melamine utilizing multi-hydrogen bonding induced charge-transfer (CT) effects. In this system, silver-2-nitro-5-mercaptobenzoic acids (Ag-TNBs) were chosen as the promising probe for melamine sensing. This method relies on the multi-hydrogen-bonding between TNB and melamine which leads to significant Raman frequency shifts in Raman spectra. When being exposure to other potential interfering substances in milk, this system exhibits high selectivity towards melamine. The limit of detection (LOD) of this method is as low as 10(-12)M, which is far below the safety of FDA and USA. The proposed method can be further applied to monitoring the amount of melamine in both caw milk and milk powder.